Immunoregulatory abnormalities have been shown to exist in a wide variety of "autoimmune" and chronic inflammatory diseases, including systemic lupus erythematosis, chronic rheumatoid arthritis, type 1 diabetes mellitus, inflammatory bowel disease, biliary cirrhosis, uveitis, multiple sclerosis and other disorders such as Crohn's disease, ulcerative colitis, bullous pemphigoid, sarcoidosis, psoriasis, ichthyosis, and Graves ophthalmopathy. Although the underlying pathogenesis of each of these conditions may be quite different, they have in common the appearance of a variety of autoantibodies and self-reactive lymphocytes. Such self-reactivity may be due, in part, to a loss of the homeostatic controls under which the normal immune system operates.
Similarly, following a bone marrow or an organ transplantation, the host lymphocytes recognize the foreign tissue antigens and begin to produce antibodies which lead to graft rejection.
One end result of an autoimmune or a rejection process is tissue destruction caused by inflammatory cells and the mediators they release. Anti-inflammatory agents, such as NSAID's (Non-Steroidal Anti-inflammatory Drugs), and corticosteroids act principally by blocking the effect of, or secretion of, these mediators, but do nothing to modify the immunologic basis of the disease. On the other hand, cytotoxic agents, such as cyclophosphamide, act in such a nonspecific fashion that both the normal and autoimmune responses are shut off. Indeed, patients treated with such nonspecific immunosuppressive agents are as likely to succumb to infection as they are to their autoimmune disease.
The cyclosporins are a family of immunosuppressive compounds isolated from fermentation broths of various fungal species, including Tolypocladium inflatum and Cyclindrocarpon lucidum.
The generic structure of the class of cyclosporins has been established as a cyclic peptide of formula I, which contains 11 amino acids. ##STR1##
Cyclosporin A, for example, shown below in formula II, contains seven N-methylated amino acids. One novel amino acid at position-1, "MeBmt", has been found to be important for the biological activity of cyclosporin. (The amino acid at position-1 is also known as the "C-9 amino acid"). We have previously found that replacing the double bond of the "C-9 amino acid" (MeBmt) with a heteroatom, such as Sulfur or Oxygen, decreases the toxicity of the parent cyclosporin. We have now found that fluorinating the amino acid at positions 2, 4, 5, 6, 7, 9, 10 and/or 11 around the ring provides potent immunosuppressive compounds, and unexpectedly in some cases, biological activity greater than that measured for cyclosporin A itself.
Biological activity is measured in terms of binding affinity for cyclophilin, the cytosolic receptor for cyclosporin (R. Handschumacher et al., Science, 226 (1984) 544), inhibition of interleukin-2 production, and inhibition of T-cell proliferation. ##STR2##
Generally, a cyclosporin, such as cyclosporin A, is not cytotoxic nor myelotoxic. It does not inhibit migration of monocytes nor does it inhibit granulocytes and macrophage action. Its action is specific and leaves most established immune responses intact. However, it is nephrotoxic and is known to cause the following undesirable side effects:
(1) abnormal liver function; PA0 (2) hirsutism; PA0 (3) gum hypertrophy; PA0 (4) tremor; PA0 (5) neurotoxicity; PA0 (6) hyperaesthesia; and PA0 (7) gastrointestinal discomfort.
Accordingly, an object of the present invention is to provide a cyclosporin analog for the care of immunoregulatory disorders and diseases, including the prevention, control and treatment thereof.
An object of the present invention is to provide new cyclosporin analogs which will (1) restore the balance of the help-and-suppression mechanism of the immune system by acting at an earlier point than the anti-inflammatory agents and (2) induce specific long-term transplantation tolerance through a suppressor cell circuit without increasing the body's susceptibility to infection.
Another object of the present invention is to provide pharmaceutical compositions for administering to a patient in need of the treatment one or more of the active immunosuppressive agents of the present invention.
Still a further object of this invention is to provide a method of controlling graft rejection, autoimmune and chronic inflammatory diseases by administering a sufficient amount of one or more of the novel immunosuppressive agents in a mammalian species in need of such treatment.
Finally, it is the object of this invention to provide processes for the preparation of the active compounds of the present invention.
A number of cyclosporins and analogs have been described in the patent literature:
U.S. Pat. No. 4,108,985 issued to Ruegger, et al. on Aug. 22, 1978 entitled, "Dihydrocyclosporin C", discloses dihydrocyclosporin C, which can be produced by hydrogenation of cyclosporin C.
U.S. Pat. No. 4,117,118 issued to Harri, et al. on Sep. 26, 1978 entitled, "Organic Compounds", discloses cyclosporins A and B, and the production thereof by fermentation.
U.S. Pat. No. 4,210,581 issued to Ruegger, et al. on Jul. 1, 1980 entitled, "Organic Compounds", discloses cyclosporin C and dihydrocyclosporin C which can be produced by hydrogenation of cyclosporin C.
U.S. Pat. No. 4,220,641, issued to Traber, et al. on Sep. 2, 1980 entitled, "Organic Compounds", discloses cyclosporin D, dihydrocyclosporin D, and isocyclosporin D.
U.S. Pat. No. 4,288,431 issued to Traber, et al. on Sep. 8, 1981 entitled, "Cyclosporin Derivatives, Their Production and Pharmaceutical Compositions Containing Them", discloses cyclosporin G, dihydrocylosporin G, and isocyclosporin G.
U.S. Pat. No. 4,289,851, issued to Traber, et al. on Sep. 15, 1981 entitled, "Process for Producing Cyclosporin Derivatives", discloses cyclosporin D, dihydrocyclosporin D, and isocyclosporin D, and a process for producing same.
U.S. Pat. No. 4,384,996, issued to Bollinger, et al. on May 24, 1983 entitled "Novel Cyclosporins", discloses cyclosporins having a .beta.-vinylene-.alpha.-amino acid residue at the 2-position and/or a .beta.-hydroxy-.alpha.-amino acid residue at the 8-position. The cyclosporins disclosed included either MeBmt or dihydro-MeBmt at the 1-position.
U.S. Pat. No. 4,396,542, issued to Wenger on Aug. 2, 1983 entitled, "Method for the Total Synthesis of Cyclosporins, Novel Cyclosporins and Novel Intermediates and Methods for their Production", discloses the synthesis of cyclosporins, wherein the residue at the 1-position is either MeBmt, dihydro-MeBmt, and protected intermediates.
U.S. Pat. No. 4,639,434, issued to Wenger, et al on Jan. 27, 1987, entitled "Novel Cyclosporins", discloses cyclosporins with substituted residues at positions 1, 2, 5 and 8.
U.S. Pat. No. 4,681,754, issued to Siegel on Jul. 21, 1987 entitled, "Counteracting Cyclosporin Organ Toxicity", discloses methods of use of cyclosporin comprising co-dergocrine.
U.S. Pat. No. 4,703,033 issued to Seebach on Oct. 27, 1987 entitled, "Novel Cyclosporins", discloses cyclosporins with substituted residues at positions 1, 2 and 3. The substitutions at position-3 include halogen.
H. Kobel and R. Traber, Directed Biosynthesis of Cyclosporins, European J. Appln. Microbiol Biotechnol., 14, 237-240 (1982), discloses the biosynthesis of cyclosporins A, B, C, D & G by fermentation.
R. Wenger, Total Synthesis--Change in Molecular Structure--Biological Effect: Cyclosporin as Example, Sandorama, 1984/111, pages 4-11, discloses methods of production of cyclosporin A.
Additional cyclosporin analogs are disclosed in a copending U.S. patent application Ser. No. 057,196 filed by B. E. Witzel on Jun. 3, 1987 (now U.S. Pat. No. 4,798,823) entitled, "New Cyclosporin Analogs with Modified "C-9 amino acids," which discloses cyclosporin analogs with sulfur-containing amino acids at position-1.
None of the above references discloses the inventive cyclosporins disclosed hereunder.